Asymptomatic primary hyperparathyroidism - need to treat?

Primary hyperparathyroidism has changed its clinical presentation from a classical disease of bone and renal stones to an asymptomatic disorder. “Classical” signs and symptoms like renal stones now occur in less than 10% of cases diagnosed and radiographic evidence of bone involvement is rare. The percentage of patients considered to be “asymptomatic” may be as high as 50%. Long-term follow-up studies of untreated patients with mild primary hyperparathyroidism showed rarely serious complications, like progressive hypercalcemia or renal complications. Based on these observation guidelines for diagnosis and conservative management for asymptomatic primary hyperparathyroidism were defined at an NIH conference in 1990 ([Anonymous, 1991]). Surgery need not be routinely recommended for patients who were 50 years old or older, whose serum calcium concentration were less than 0.25 to 0.40 mmol/l above the upper limit of normal, and who had no hypercalciuria, nephrolithiasis, renal insufficiency, or osteopenia.

Lines of evidence accumulate within the last ten years showing that the majority of patients with only mild hypercalcemia are not entirely asymptomatic. They suffer from a variety of mild and non-specific symptoms like nausea, constipation, vague muscle pains, lethargy and mental confusion. Such “nonclassical or associated” symptoms are often attributed to the aging process and are rarely subject of patients complaints. Other associated disorders, such as cardiovascular diseases like hypertension, progressive osteopenia, peptic ulcer disease, gout and depression have been associated with primary hyperparathyroidism. However, it may be possible that these and other non traditional features are linked to the abnormal calcium homeostasis. As parathyroidectomy is the only effective treatment for primary hyperparathyroidism, the question arises whether these mild symptoms and associated disorders can be improved by successful parathyroidectomy.

In a case control study with patients with primary hyperparathyroidism and euthyroid thyroid nodular disease subtle symptoms were detected with symptom questionnaires in over 90% in a group with mild to moderate hypercalcemia studied before surgery ([Chan et al., 1995]). Patients demonstrated symptomatic improvement after parathyroidectomy, in contrast to control patients who underwent thyroidectomy for benign nontoxic disease. These results are confirmed by a study using the SF 36 Health Status Questionaire pre- and postoperatively in primary hyperparathyroidism patients with mild and severe hypercalcemia ([Burney et al., 1999]).The score in patients with mild hypercalcemia was as low initially and improved as much as the scores in patients with more severe hypercalcemia. In this issue of ECED Hasse et al., 2000 confirmed in a cohort study the observation that real “asymptomatic” patients with primary hyperparathyroidism are rare (9%) and that postoperative improvement is seen in 81% of “asymptomatic” (defined by NIH criteria) patients. Many apparently asymptomatic patients will only realise that they did in fact have preoperative symptoms in retrospect, following parathyroidectomy. By their mild nature it is quite difficult to predict which specific symptoms will improve and to what extent. This makes individual risk-benefit assessment difficult.

Patients without classical symptoms may well have adverse metabolic effects of primary hyperparathyroidism such as osteopenia. Biochemical markers of bone formation such as bone alkaline phosphatase activity and osteocalcin, and markers of bone resorption such as hydroxypyridinium crosslinks of collagen, are typically increased. PTH has a catabolic effect especially on cortical bone often seen in decreased bone density at the radius or femoral neck site. Surgical cure of hyperparathyroidism led to a prompt and substantial increase in bone density ([Silverberg et al., 1999]). This is of special importance in postmenopausal women who make up at least one half of all patients with primary hyperparathyroidism.

Patients with primary hyperparathyroidism have an increased risk of death mainly due to cardiovascular disease and cancer. Two population-based Swedish studies have demonstrated excess long-term mortality in relatively mildly affected unoperated patients ([Palmer et al., 1987]; [Leifsson et al., 1996]). Most studies have suggested that even after parathyroidectomy, there is a residual excess risk of mortality ([Lind et al., 1991], [Hedbäck et al., 1998], [Palmer et al., 1987]), but the excess mortality rate gradually declined after parathyroidectomy especially in patients with mild hypercalcemia to that of the general population. Patients with primary hyperparathyroidism showed a high incidence of left ventricular hypertrophy and cardiac calcification deposits ([Stefenelli et al., 1997]). After parathyroidectomy a regression of hypertrophy as well as no evidence of progression of the calcifications was observed. The increased mortality obviously is a strong argument in favour of surgery in patients even with asymptomatic primary hyperparathyroidism. Surgery can be performed safely with a minimal complication rate and a high success rate of probably more than 95%. The magnitude of the potential reduction of long-term mortality by surgery probably substantially exceeds the extremely low mortality of parathyroidectomy.

There is little debate about the primacy of surgery in the management of classical primary hyperparathyroidism. The adverse health effects of untreated mild primary hyperparathyroidism are likely to be non traditional, such as increases in cardiovascular mortality, in the prevalence of neurobehaviour and psychiatric morbidity and of osteopenia. The prevalence of nonclassical sympoms and the demonstration of reversibility by parathyroidectomy strengthen the argument for surgery in such patients. The advances in parathyroid gland identification by techneticum-99m sestamibi imaging and removal by intraoperative measurement of PTH make surgical treatment simpler and faster than in the past. Parathyroidectomy should now be recommended for nearly all patients with primary hyperparathyroidism.

References

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• 3 Chan A K, Duh Q Y, Katz M H, Siperstein A E, Clark O H. Clinical manifestation of primary Hyperparathyroidism before and after parathyroidectomy.  Ann Surg. 222 402-413 1995; 
• 4 Hasse C, Sitter H, Bachmann S, Zielke A, Koller M, Nies C, Lorenz W, Rothmund M. How asymptomatic is asymptomatic primary hyperparathyroidism?.  Exp Clin Endocrinol Diabetes. 108 265-274 2000; 
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• 7 Lind L, Jacobson S, Palmer M, Lithell H, Wengle B, Ljunghall S. Cardiovascular risk factors in primary hyperparathyroidism: a 15 year follow-up of operated and unoperated cases.  J Intern Med. 230 29-35 1991; 
• 8 Palmer M, Bergstrom R, Akerstrom G, Adami H, Jakobsson S, Ljunghall S. Survival and renal function in untreated hypercalcemia. Population-based cohort study with 14 years of follow-up.  Lancet. O 59-62 1987; 
• 9 Silverberg S J, Shane E, Jacobs T P, Siris E, Bilezikian J P. A 10-year prospective study of primary hyperparathyroidism with and without parathyroid surgery.  N Engl J Med. 341 1249-1255 1999; 
• 10 Stefenelli T, Abela C, Frank H, Koller-Strametz J, Globits S, Bergler-Klein J, Niederle B. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up.  J Clin Endocrinol Metab. 82 106-112 1997;